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The Regulatory Repertoire of Pseudomonas aeruginosa AmpC ß-Lactamase Regulator AmpR Includes Virulence Genes
Department of Biological Sciences
  • Deepak Balasubramania, Department of Biological Sciences, Florida International University
  • Lisa Schneper, Herbert Werthiem College of Medicine, Florida International University
  • Massimo Merighi, Harvard Medical School
  • Roger Smith, Harvard Medical School
  • Giri Narasimhan, School of Computing and Information Sciences, Florida International University
  • Stephen Lory, Harvard Medical School
  • Kalai Mathee, Herbert Wertheim College of Medicine, Florida International University
Date of this Version
3-29-2012
Document Type
Article
Disciplines
Abstract
In Enterobacteriaceae, the transcriptional regulator AmpR, a member of the LysR family, regulates the expression of a chromosomal b-lactamase AmpC. The regulatory repertoire of AmpR is broader in Pseudomonas aeruginosa, an opportunistic pathogen responsible for numerous acute and chronic infections including cystic fibrosis. In addition to regulating ampC, P. aeruginosa AmpR regulates the sigma factor AlgT/U and production of some quorum sensing (QS)- regulated virulence factors. In order to better understand the ampR regulon, we compared the transcriptional profile generated using DNA microarrays of the prototypic P. aeruginosa PAO1 strain with its isogenic ampR deletion mutant, PAODampR. Transcriptome analysis demonstrates that the AmpR regulon is much more extensive than previously thought, with the deletion of ampR influencing the differential expression of over 500 genes. In addition to regulating resistance to blactam antibiotics via AmpC, AmpR also regulates non-b-lactam antibiotic resistance by modulating the MexEF-OprN efflux pump. Other virulence mechanisms including biofilm formation and QS-regulated acute virulence factors are AmpRregulated. Real-time PCR and phenotypic assays confirmed the microarray data. Further, using a Caenorhabditis elegans model, we demonstrate that a functional AmpR is required for P. aeruginosa pathogenicity. AmpR, a member of the core genome, also regulates genes in the regions of genome plasticity that are acquired by horizontal gene transfer. Further, we show differential regulation of other transcriptional regulators and sigma factors by AmpR, accounting for the extensive AmpR regulon. The data demonstrates that AmpR functions as a global regulator in P. aeruginosa and is a positive regulator of acute virulence while negatively regulating biofilm formation, a chronic infection phenotype. Unraveling this complex regulatory circuit will provide a better understanding of the bacterial response to antibiotics and how the organism coordinately regulates a myriad of virulence factors in response to antibiotic exposure.
Comments

Copyright (c) 2012 Balasubramanian et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

doi:10.1371/journal.pone.0034067

Citation Information
Balasubramanian D, Schneper L, Merighi M, Smith R, Narasimhan G, et al. (2012) The Regulatory Repertoire of Pseudomonas aeruginosa AmpC ß- Lactamase Regulator AmpR Includes Virulence Genes. PLoS ONE 7(3): e34067. doi:10.1371/journal.pone.0034067